Sunday, 13 November 2011

Vitamins, genes and language

Thiamine chloride (source: Wikipedia)

In November 2003, a
six-month-old boy was admitted to the emergency department of a children’s hospital in Tel Aviv. He had
been vomiting daily for two months, was apathetic, and had not responsed to
anti-emetic drugs. The examining doctor noticed something odd about the child’s
eye movements and referred him on to the neuro-ophthalmology department. A
brain scan failed to detect any tumour. The doctors remembered a case they had
seen 18 months earlier, where a 16-year-old girl had presented with episodic
vomiting and abnormal eye movements due to vitamin B1 deficiency. They injected the child with thiamine and saw
improvement after 36 hours. The vomiting stopped, and over the next six weeks
the eye movements gradually normalised. When followed up 18 months later he was
judged to be completely normal.

This
was not, however, an isolated case. Other babies in Israel were turning up in emergency
departments with similar symptoms. Where thiamine deficiency was promptly
recognised and treated, outcomes were generally good, but two children
died and others were left with seizures and neurological impairment. But
why were they thiamine deficient? All
were being fed the same kosher, non-dairy infant formula, but it contained
thiamine. Or did it? Analysis of samples by the Israeli Ministry of Health
revealed that levels of
thiamine in this product were barely detectable, and there was an immediate
product recall. The manufacturer confirmed that human error had led to thiamine
being omitted when the formula had been altered.

The
cases who had been hospitalised were just the tip of the iceberg. Up to 1000
infants had been fed the formula. Most of these children had shown no signs of neurological
problems. But a
recent study reported in Brain describes a remarkable link between this
early thiamine deprivation and later language development. Fattal and
colleagues studied 59 children who had been fed thiamine-deficient formula for
at least one month before the age of 13
months, but who were regarded as neurologically asymptomatic. Children who had
birth complications or hearing loss were excluded. The authors stress that the
children were selected purely on the basis of their exposure to the deficient
formula, and not according to their language abilities. All were attending
regular schools. A control group of 35
children was selected from the same health centres, matched on age.

Children
were given a range of language tests when they were 5 to 7 years of
age. These included measures of sentence comprehension, sentence production,
sentence repetition and naming. There were dramatic differences between the two
groups of children, with the thiamine-deficient group showing deficits in all
these tasks. The authors argued that the profile of performance was identical
to that seem in children with a diagnosis of specific language impairment
(SLI), with specific problems with certain complex grammatical constructions,
and normal performance on a test of conceptual understanding that did not
involve any language.

Figure 1 An example of a picture pair used
in the comprehension task.

The child is asked to point to the picture that
matches a sentence,

such as ‘Tar’e li et ha-yalda she-ha-isha
mecayeret’

(Show me the girl that the woman draws).
From Fattal et al, 2011.

I
have some methodological quibbles with the paper. The authors excluded three
control children who did poorly on the syntactic tests because they were
outliers - this seems wrong-headed if the aim is to see whether syntactic
problems are more common in children with thiamine-deficiency than in those
without. The non-language conceptual
tests were too easy, with both groups scoring above 95% correct. To convince me
that the children had normal abilities they would need to demonstrate no
difference between groups on a sensitive test of nonverbal IQ. My own
experience of testing children’s grammatical abilities in English is that
ability to do tests such as that shown in Figure 1 can be influenced by
attention and memory as well as syntactic ability, and so I think we need to
rule out other explanations before accepting the linguistic account offered by
the authors. I’d also have liked a bit more information about how the control
children were recruited, to be certain they were not a ‘supernormal’ group - often
a problem with volunteer samples, and something that could have been addressed
if a standarized IQ test had been used. But overall, the effects demonstrated
by these authors are important, given that there are so few environmental factors known to selectively affect language skills. These results raise a number of questions about children’s
language impairments.

The
first question that struck me was whether thiamine deficiency might be
implicated in other cases outside this rare instance. I have no expertise in
this area, but this paper prompted me to seek out other reports. I learned that
thiamine deficiency, also known as
infantile beriberi, is extremely rare in the developed world, and when it
does occur it is usually because an infant is breastfeeding from a mother who
is thiamine deficient. It is therefore important to stress that thiamine deficiency is highly unlikely to
be implicated in cases of specific language impairment in Western societies.
However, a
recent paper reported that it is relatively common in Vientiane, Laos, where there are traditional
taboos against eating certain foods in the period after giving birth. The researchers
suggested that obvious cases with neurological impairments may be the extreme
manifestation of a phenomenon that is widespread in milder form. If so, then
the Israeli paper suggests that the problem may be even more serious than originally suggested, because there could be longer-term adverse effects on language
development in those who are symptom-free in infancy.

The
second question concerns the variation in outcomes of thiamine-deficient
infants. Why, when several hundred children had been fed the deficient formula, were only some of them severely affected? An obvious possibility is the extent to which infants were fed
foods other than the deficient formula. But there may also be genetic
differences between children in how efficiently they process thiamine.

This
brings us to the third question: could this observed link between thiamine
deficiency and language impairment have relevance for genetic studies of language difficulties? Twin
and family studies have indicated that specific language impairment is
strongly influenced by genes. However, one seldom finds genes that have a major
all-or-none effect. Rather, there are genetic risk variants that have a fairly
modest and probabilistic impact on language ability.

Robinson Crusoe Island

A
recent study by Villanueva
et al illustrates this point. They analysed genetic variation in an
isolated population on Robinson Crusoe
Island, the only inhabited island in the Juan
Fernandez Archipelago, 677 km to the west of Chile. At the time of the study
there were 633 inhabitants, most of whom were descended from a small number of
founder indviduals. This population is of particular interest to geneticists as
there is an unusually high rate of specific language impairment. A genome-wide analysis failed to identify any
single major gene that distinguished affected from unaffected individuals.
However, there was a small region of chromosome 7 where there genetic structure
was statistically different between affected and unaffected cases, and which
contained genetic variants that had previously been found linked to language
impairments in other samples. One of these, TPK1 is involved in the catalysis
of the conversion of thiamine to thiamine pyrophosphate. It must be stressed
that the genetic association between a thiamine-related genetic variant
and language impairment isprobabilistic and weak, and far more research
will be needed to establish whether it is generalises beyond the rare
population studied by Villanueva and colleagues. But this observation points
the way to a potential mechanism by which a genetic variant could influence
language development.

To sum up: the
importance of the study by Fattal and colleagues is two-fold. First, it
emphasises the extent to which there can be adverse longer-term consequences of
thiamine deficiency in children who may not have obvious symptoms, an
observation which may assume importance in cultures where there is inadequate
nutrition in breast-feeding mothers. Second, it highlights a role of thiamine
in early neurodevelopment, which may prove an
important clue to neuroscientists and geneticists investigating risks for language impairment.

References

Fattal I, Friedmann N, & Fattal-Valevski A (2011). The crucial role of thiamine in the development of syntax and lexical retrieval: a study of infantile thiamine deficiency. Brain : a journal of neurology, 134 (Pt 6), 1720-39 PMID: 21558277